Aldosterone, which regulates renal
salt retention, is synthesized in adrenocortical mitochondria in response to
angiotensin II. Excess
aldosterone causes myocardial injury and
heart failure, but potential intracardiac
aldosterone synthesis has been controversial. We hypothesized that the stressed heart might produce
aldosterone. We used blue native gel electrophoresis, immunoblotting,
protein crosslinking, coimmunoprecipitations, and mass spectrometry to assess rat cardiac
aldosterone synthesis. Chronic infusion of
angiotensin II increased circulating
corticosterone levels 350-fold and induced cardiac
fibrosis.
Angiotensin II doubled and
telmisartan inhibited
aldosterone synthesis by heart mitochondria and cardiac production of
aldosterone synthase (
P450c11AS). Heart
aldosterone synthesis required
P450c11AS, Tom22 (a mitochondrial translocase receptor), and the intramitochondrial form of the
steroidogenic acute regulatory protein (StAR);
protein crosslinking and coimmunoprecipitation studies showed that these three
proteins form a 110-kDa complex. In steroidogenic cells, extramitochondrial (37-kDa) StAR promotes
cholesterol movement from the outer to inner mitochondrial membrane where
cholesterol side-chain cleavage enzyme (P450scc) converts
cholesterol to
pregnenolone, thus initiating steroidogenesis, but no function has previously been ascribed to intramitochondrial (30-kDa) StAR; our data indicate that intramitochondrial 30-kDa StAR is required for
aldosterone synthesis in the heart, forming a trimolecular complex with Tom22 and
P450c11AS. This is the first activity ascribed to intramitochondrial StAR, but how this promotes
P450c11AS activity is unclear. The stressed heart did not express P450scc, suggesting that circulating
corticosterone (rather than intracellular
cholesterol) is the substrate for cardiac
aldosterone synthesis. Thus, the stressed heart produced
aldosterone using a previously undescribed intramitochondrial mechanism that involves
P450c11AS, Tom22, and 30-kDa StAR. SIGNIFICANCE STATEMENT: Prior studies of potential cardiac
aldosterone synthesis have been inconsistent. This study shows that the stressed rat heart produces
aldosterone by a novel mechanism involving
aldosterone synthase, Tom22, and intramitochondrial
steroidogenic acute regulatory protein (StAR) apparently using circulating
corticosterone as substrate. This study establishes that the stressed rat heart produces
aldosterone and for the first time identifies a biological role for intramitochondrial 30-kDa StAR.